This application focuses on the interface between Alzheimer's disease (AD) genetics, inflammation and the gut microbiome. APOE alleles are the most impactful AD genetic risk factor and modulate several pathways including inflammation. Microglial function itself is clearly linked to AD risk by TREM2 and CD33 single nucleotide polymorphisms (SNP)s. Hence, agents that modulate microglial function are excellent candidates to modulate AD risk. Recently, a gut microbiome metabolite, short chain fatty acids (SCFA)s, have emerged as promoting microglial function. The possibility that the microbiome may modulate AD is supported by findings that AD-related phenotypes are reduced in APP mice treated with antibiotics or maintained in a gnotobiotic environment. Here, we propose a novel link between AD genetics and the gut microbiome. This study resulted from a serendipitous meeting at an APOE conference with Richard Guerrant, who described his studies showing that gut health in humans and mice is associated with APOE genotype; when humans in a third world environment suffer from diarrheal outbreaks, APOE4 carriers have less severe disease and better outcomes, relative to APOE3 individuals. Similar findings were found in the widely used, APOE targeted replacement (TR) murine model wherein APOE4 was associated with an improved response to gastrointestinal infection and undernourishment, compared to APOE3. The possibility that APOE alters the gut microbiome is also supported by a report of microbiome variation between wild- type and APOE deficient mice. Considering these findings, we propose the global hypothesis that APOE alleles modulate the gut microbiome and that this contributes to APOE allelic effects on AD risk. As a corollary, we further hypothesize that changing the microbiome to that of APOE2 individuals will reduce AD risk. To evaluate this scientific premise, we submit the following Specific Aims: 1. Test the hypothesis that the gut microbiome is associated with APOE genotype in a murine model. Our preliminary results show a striking stepwise pattern in microbiome profiles from APOE2 to APOE3 to APOE4, with Ruminococcaceae highest in APOE2. 2. Test the hypothesis that the gut microbiome is associated with APOE genotype in humans. 3. Test the hypothesis that the gut microbiomes associated with APOE2 and APOE4 have opposing effects on AD-related phenotypes. If successful, we expect this interdisciplinary proposal to demonstrate (i) an APOE2-associated microbiome ameliorates AD-related phenotypes and (ii) dietary resistant starch mimics APOE2 effects on the microbiome, SCFA levels, microglial activation, amyloid burden and cognition in a murine model. Since resistant starch has been shown to increase Ruminococcaceae and SCFAs in humans, such results may be directly translatable to human trials.